Human Milk Micronutrients and Child Growth and Body Composition in the First 2 years: A Systematic Review.

Human milk (HM) provides a plethora of nutritional and non-nutritional compounds that support infant development. For many compounds, concentrations vary substantially among mothers and across lactation, and their impact on infant growth is poorly understood. We systematically searched MEDLINE, Embase, the Cochrane Library, Scopus, and Web of Science to synthesize evidence published between 1980 and 2022 on HM components and anthropometry through 2 y of age among term-born infants. Outcomes included weight-for-length, length-for-age, weight-for-age, body mass index (in kg/m2)-for-age, and growth velocity. From 9992 abstracts screened, 144 articles were included and categorized based on their reporting of HM micronutrients, macronutrients, or bioactive components. Micronutrients (vitamins and minerals) are reported here, based on 28 articles involving 2526 mother-infant dyads. Studies varied markedly in their designs, sampling times, geographic and socioeconomic settings, reporting practices, and the HM analytes and infant anthropometrics measured. Meta-analysis was not possible because data were sparse for most micronutrients. The most-studied minerals were zinc (15 articles, 1423 dyads) and calcium (7 articles, 714 dyads). HM iodine, manganese, calcium, and zinc concentrations were positively associated with several outcomes (each in ≥2 studies), whereas magnesium (in a single study) was negatively associated with linear growth during early lactation. However, few studies measured HM intake, adjusted for confounders, provided adequate information about complementary and formula feeding, or adequately described HM collection protocols. Only 4 studies (17%) had high overall quality scores. The biological functions of individual HM micronutrients are likely influenced by other HM components; yet, only 1 study analyzed data from multiple micronutrients simultaneously, and few addressed other HM components. Thus, available evidence on this topic is largely inconclusive and fails to address the complex composition of HM. High-quality research employing chronobiology and systems biology approaches is required to understand how HM components work independently and together to influence infant growth and to identify new avenues for future maternal, newborn, or infant nutritional interventions.

Human Milk Macronutrients and Child Growth and Body Composition in the First Two Years: A Systematic Review.

Among exclusively breastfed infants, human milk (HM) provides complete nutrition in the first mo of life and remains an important energy source as long as breastfeeding continues. Consisting of digestible carbohydrates, proteins, and amino acids, as well as fats and fatty acids, macronutrients in human milk have been well studied; however, many aspects related to their relationship to growth in early life are still not well understood. We systematically searched Medline, EMBASE, the Cochrane Library, Scopus, and Web of Science to synthesize evidence published between 1980 and 2022 on HM components and anthropometry through 2 y of age among term-born healthy infants. From 9992 abstracts screened, 57 articles reporting observations from 5979 dyads were included and categorized based on their reporting of HM macronutrients and infant growth. There was substantial heterogeneity in anthropometric outcome measurement, milk collection timelines, and HM sampling strategies; thus, meta-analysis was not possible. In general, digestible carbohydrates were positively associated with infant weight outcomes. Protein was positively associated with infant length, but no associations were reported for infant weight. Finally, HM fat was not consistently associated with any infant growth metrics, though various associations were reported in single studies. Fatty acid intakes were generally positively associated with head circumference, except for docosahexaenoic acid. Our synthesis of the literature was limited by differences in milk collection strategies, heterogeneity in anthropometric outcomes and analytical methodologies, and by insufficient reporting of results. Moving forward, HM researchers should accurately record and account for breastfeeding exclusivity, use consistent sampling protocols that account for the temporal variation in HM macronutrients, and use reliable, sensitive, and accurate techniques for HM macronutrient analysis.

Human Milk Bioactive Components and Child Growth and Body Composition in the First 2 Years: A Systematic Review.

Human milk (HM) contains macronutrients, micronutrients, and a multitude of other bioactive factors, which can have a long-term impact on infant growth and development. We systematically searched MEDLINE, EMBASE, Cochrane Library, Scopus, and Web of Science to synthesize evidence published between 1980 and 2022 on HM components and anthropometry through 2 y of age among term-born infants. From 9992 abstracts screened, 141 articles were included and categorized based on their reporting of HM micronutrients, macronutrients, or bioactive components. Bioactives including hormones, HM oligosaccharides (HMOs), and immunomodulatory components are reported here, based on 75 articles from 69 unique studies reporting observations from 9980 dyads. Research designs, milk collection strategies, sampling times, geographic and socioeconomic settings, reporting practices, and outcomes varied considerably. Meta-analyses were not possible because data collection times and reporting were inconsistent among the studies included. Few measured infant HM intake, adjusted for confounders, precisely captured breastfeeding exclusivity, or adequately described HM collection protocols. Only 5 studies (6%) had high overall quality scores. Hormones were the most extensively examined bioactive with 46 articles (n = 6773 dyads), compared with 13 (n = 2640 dyads) for HMOs and 12 (n = 1422 dyads) for immunomodulatory components. Two studies conducted untargeted metabolomics. Leptin and adiponectin demonstrated inverse associations with infant growth, although several studies found no associations. No consistent associations were found between individual HMOs and infant growth outcomes. Among immunomodulatory components in HM, IL-6 demonstrated inverse relationships with infant growth. Current research on HM bioactives is largely inconclusive and is insufficient to address the complex composition of HM. Future research should ideally capture HM intake, use biologically relevant anthropometrics, and integrate components across categories, embracing a systems biology approach to better understand how HM components work independently and synergistically to influence infant growth.

Patient Experience with Telemedicine in Adults with Congenital Heart Disease.

Introduction: The COVID-19 pandemic has resulted in increased use of telemedicine. There are limited data on patient experience with telemedicine in adults with congenital heart disease (ACHD). We hypothesized that due to their complex medical history, ACHD would prefer in-person clinic visits over telemedicine. Methods: We conducted a nurse-administered telephone survey based on Agency for Healthcare Research and Quality recommendations to assess patient experience after ACHD telemedicine visits in the early part of the pandemic from March 2020 to June 2020. Results: Of 216 ACHD who had telemedicine visits, 136 (63%) agreed to participate in the survey. Mean age was 45 ± 18 years, majority (65%) being video encounters. Most (98%) patients expressed that the telemedicine visit was successful in addressing their health care needs. Only 21 (15%) patients reported technical issues. Most patients (76%) preferred telemedicine given testing was provided separately, 25 (18%) preferred in-person clinic visits, and 8 (6%) had no preference. Of the 25 patients over 65 years, 19 (76%) would choose telemedicine over the in-person clinic, and only 1 patient reported technical difficulties. Conclusion: ACHD reported a positive experience with telemedicine. Technical limitations were infrequent even among the elderly. The majority of patients felt that their health care needs were addressed and would consider telemedicine over clinic visits. These data are important as payors move away from supporting telemedicine and hospitals restructure, with and without ongoing COVID-19 concerns.

Genosets for APOE and CYP7A1-rs3808607 variants do not predict LDL cholesterol lowering upon intervention with plant sterols in a randomized, double-blind, placebo-controlled trial.

BACKGROUND: The consumption of 2 g/d plant sterols (PSs) reduces circulating LDL cholesterol by ≤10%. The degree of LDL cholesterol lowering was associated with specific apolipoprotein E [APOE, Reference SNP (rs)429358] and cholesterol 7α-hydroxylase (CYP7A1, rs3808607) genosets in previous post hoc analyses of randomized controlled trials. However, because post hoc analyses do not conform to the randomization model, there is a greater potential that the findings could be due to type I error, thus warranting validation through an a priori-designed intervention trial. OBJECTIVES: The GenePredict Plant Sterol study (GPS) was designed to validate associations of LDL cholesterol lowering with specific APOE and CYP7A1 genosets through a priori recruitment of individuals carrying prespecified genosets. METHODS: A 2-center, double-blind, placebo-controlled, randomized 2-period crossover dietary intervention with 2 g/d PS for 28 d with a minimum 28-d washout was undertaken from July 2017 to December 2019. A priori recruitment of individuals with slightly elevated LDL cholesterol was based on genosets of APOE isoforms and CYP7A1 rs3808607. Randomization was performed with stratification by sex and genoset. RESULTS: The recruitment target of 64 participants with prespecified genosets could not be reached, despite the screening of 477 individuals; 42 participants completed the intervention trial. Reductions in LDL cholesterol were similar across all 3 genosets (-0.298 ± 0.164, -0.357 ± 0.115, -0.293 ± 0.109 mmol/L; P = 0.0002 overall; P = 0.9126 for treatment × genoset), providing evidence that the shortfall in recruitment might not have stopped the trial from meeting the objective. CONCLUSIONS: APOE and CYP7A1 genotypes did not influence the efficacy of LDL cholesterol reductions upon dietary intervention with PSs. Findings of previous post hoc analyses could not be validated in a trial using a priori genotype-based recruitment. Obtaining adequate numbers of participants is challenging in trials using genoset-based recruitment, even for common variants.

Efficacy and safety of clinically managed weight loss programs: a systematic review and meta-analysis protocol.

BACKGROUND: Obesity has become a major driver in the burden of chronic diseases. The Canadian Clinical Practice Guidelines recommend a lifestyle intervention for the management and prevention of obesity. This includes behavior modification, dietary counseling, and physical activity. With the market overwhelmed with weight loss programs, the majority are focused on low-calorie diets and general recommendations for exercise. Most are not personalized and are not administered by healthcare professionals. An interdisciplinary team of highly trained healthcare professionals has the ability to provide medically sound and safe advice in all aspects of an individuals' life, such as lifestyle, sleep, mental health, and behaviors. A clinically managed weight loss program is defined as a team including a dietitian, exercise professional, psychologist, and/or physician or nurse practitioner oversight. With limiting results in the literature regarding clinically managed weight loss programs, it is difficult to conclude whether it may be effective. Therefore, the objective of this systematic review is to assess clinically managed weight loss programs, with a physician or nurse practitioner oversight in comparison with non-clinically managed weight loss programs with no physician oversight or nurse practitioner oversight in adults who are living with overweight or obesity. METHODS: A literature search will be executed by a knowledge synthesis librarian on MEDLINE, Cochrane Central, Embase, PsycINFO, and CINAHL. The data collected will be extracted, stored, and managed in MS Excel 2016. The extraction of the data will include study details, study population details, health team details, intervention details, and outcome details. DISCUSSION: The prevalence of obesity has been increasing throughout the decades. The results from this systematic review may aid in recommending a more clinically safe weight loss program for those who struggle with overweight or obesity. SYSTEMATIC REVIEW REGISTRATION: PROSPERO CRD42020170014.

Genetic basis for prediction of non-responders to dietary plant sterol intervention (GenePredict-PS): a study protocol for a double-blind, placebo-controlled, randomized two-period crossover study.

BACKGROUND: Functional food ingredients and natural health products have been demonstrated to reduce disease risk and thereby help to lower health care costs across populations at risk for chronic or degenerative diseases. However, typically a wide range of interindividual variability exists in response across individuals to nutritional and natural health product bioactives, such as plant sterols (PS). This study aims to determine and utilize information on the associations between genosets and the degree of responsiveness to dietary PS intervention, with a long-term objective of developing genetic tests to predict responses to PS. METHODS: This clinical trial is designed as a double-blind, placebo controlled, randomized two-period crossover study. Sixty-four eligible participants with the specific a priori-determined single nucleotide polymorphisms (SNPs) associated with a responsiveness to PS will consume PS or a placebo treatment for two 4-week periods. The PS treatment consists of two daily single portions of margarine, each providing 1 g PS during the PS period (2.0 g/day of PS in total). The placebo will be an identical margarine containing no added PS. Low-density lipoprotein cholesterol (LDL-C) responsiveness to the controlled administration of PS will be investigated as the primary outcome, and the associations between interindividual genoset variabilities and response to PS consumption will be determined. DISCUSSION: This research will provide further insight into whether the associations between previously identified SNPs and the response of LDL-C to PS consumption can be used in a predictive manner. It will also provide insight into the complexities of undertaking a nutrigenetic trial with prospective recruitment based on genotype. TRIAL REGISTRATION: ClinicalTrials.gov: Identifier: NCT02765516. Registered on 6 May 2016.

The Manitoba Personalized Lifestyle Research (TMPLR) study protocol: a multicentre bidirectional observational cohort study with administrative health record linkage investigating the interactions between lifestyle and health in Manitoba, Canada.

INTRODUCTION: Lifestyle factors, such as diet, physical activity and sleep, are associated with the development of many chronic diseases. The objective of The Manitoba Personalized Lifestyle Research study is to understand how these lifestyle factors interact with each other and with other factors, such as an individual's genetics and gut microbiome, to influence health. METHODS: An observational study of adults, with extensive phenotyping by objective health and lifestyle assessments, and retrospective assessment of early life experiences, with retrospective and prospective utilisation of secondary data from administrative health records. STUDY POPULATION: A planned non-random convenience sample of 840 Manitobans aged 30-46 recruited from the general population, stratified by sex (equal men and women), body mass index (BMI; 60% of participants with a BMI>25 kg/m2) and geography (25% from rural areas). These stratifications were selected based on Manitoba demographics. MEASUREMENTS: Lifestyle factors assessed will include dietary pattern, physical activity, cardiovascular fitness, and sleep. Factors such as medical history, socioeconomic status, alcohol and tobacco consumption, cognition, stress, anxiety, and early life experiences will also be documented. A maternal survey will be performed. Body composition and bone density will be measured by dual energy X-ray absorptiometry. Blood pressure, pulse wave velocity, and augmentation index will be measured on two consecutive days. Chronic disease risk biomarkers will be measured in blood and urine samples. DNA will be extracted for genetic analysis. A faecal sample will be collected for microbiome analysis. Participants may provide their Manitoba personal health information number to link their study data with administrative health records. ETHICS AND DISSEMINATION: Ethics approval has been obtained from the University of Manitoba Health Research Ethics Board (protocol # HS18951; 05/01/2016). Data analysis, release of results and publication of manuscripts are scheduled to start in early 2019. Additional information at www.TMPLR.ca. TRIAL REGISTRATION NUMBER: NCT03674957; Pre-results.

Distinct disruptions in Land's cycle remodeling of glycerophosphocholines in murine cortex mark symptomatic onset and progression in two Alzheimer's disease mouse models.

Changes in glycerophosphocholine metabolism are observed in Alzheimer's disease; however, it is not known whether these metabolic disruptions are linked to cognitive decline. Here, using unbiased lipidomic approaches and direct biochemical assessments, we profiled Land's cycle lipid remodeling in the hippocampus, frontal cortex, and temporal-parietal-entorhinal cortices of human amyloid beta precursor protein (ΑßPP) over-expressing mice. We identified a cortex-specific hypo-metabolic signature at symptomatic onset and a cortex-specific hyper-metabolic signature of Land's cycle glycerophosphocholine remodeling over the course of progressive behavioral decline. When N5 TgCRND8 and ΑßPPSwe /PSIdE9 mice first exhibited deficits in the Morris Water Maze, levels of lyso-phosphatidylcholines, LPC(18:0/0:0), LPC(16:0/0:0), LPC(24:6/0:0), LPC(25:6/0:0), the lyso-platelet-activating factor (PAF), LPC(O-18:0/0:0), and the PAF, PC(O-22:6/2:0), declined as a result of reduced calcium-dependent cytosolic phospholipase A2 α (cPLA2 α) activity in all cortices but not hippocampus. Chronic intermittent hypoxia, an environmental risk factor that triggers earlier learning memory impairment in ΑßPPSwe /PSIdE9 mice, elicited these same metabolic changes in younger animals. Thus, this lipidomic signature of phenoconversion appears age-independent. By contrast, in symptomatic N5 TgCRND8 mice, cPLA2 α activity progressively increased; overall Lyso-phosphatidylcholines (LPC) and LPC(O) and PC(O-18:1/2:0) levels progressively rose. Enhanced cPLA2 α activity was only detected in transgenic mice; however, age-dependent increases in the PAF acetylhydrolase 1b α1 to α2 expression ratio, evident in both transgenic and non-transgenic mice, reduced PAF hydrolysis thereby contributing to PAF accumulation. Taken together, these data identify distinct age-independent and age-dependent disruptions in Land's cycle metabolism linked to symptomatic onset and progressive behavioral decline in animals with pre-existing Αß pathology. OPEN SCIENCE BADGES: This article has received a badge for *Open Materials* because it provided all relevant information to reproduce the study in the manuscript. The complete Open Science Disclosure form for this article can be found at the end of the article. More information about the Open Practices badges can be found at https://cos.io/our-services/open-science-badges/.

Dietary Vitamin C in Human Health.

Vitamin C is essential to prevent scurvy in humans and is implicated in the primary prevention of common and complex diseases such as coronary heart disease, stroke, and cancer. This chapter reviews the latest knowledge about dietary vitamin C in human health with an emphasis on studies of the molecular mechanisms of vitamin C maintenance as well as gene-nutrient interactions modifying these relationships. Epidemiological evidence indicates 5% prevalence for vitamin C deficiency and 13% prevalence for suboptimal status even in industrialized countries. The daily intake (dose) and the corresponding systemic concentrations (response) are related in a saturable relationship, and low systemic vitamin C concentrations in observational studies are associated with negative health outcomes. However, there is no evidence that vitamin C supplementation impacts the risks for all-cause mortality, impaired cognitive performance, reduced quality of life, the development of eye diseases, infections, cardiovascular disease, and cancers. This might be related to the fact that prevention would not be realized by supplementation in populations already adequately supplied through dietary sources. Recent genetic association studies indicate that the dietary intake might not be the sole determinant of systemic concentrations, since variations in genes participating in redox homeostasis and vitamin C transport had been associated with lowered plasma concentrations. However, impact sizes are generally low and these phenomena might only affect individual of suboptimal dietary supply.

Effect of Daily Iron Supplementation in Healthy Exclusively Breastfed Infants: A Systematic Review with Meta-Analysis.

BACKGROUND: The literature on the iron requirements of exclusively breastfed infants contains conflicting data and contrary views. OBJECTIVE: The purpose of this study was to summarize the evidence for both benefits and risks of daily oral iron supplementation with regard to hematologic, growth, cognitive parameters, and adverse effects in exclusively breastfed infants. MATERIALS AND METHODS: Structured electronic searches were conducted using PubMed, Cochrane Library databases, and Google Scholar for randomized controlled trials (RCTs) involving daily iron supplementation in full-term healthy exclusively breastfed infants. Random- and fixed-effects models were used for calculating the pooled estimates. RESULTS: Four RCTs with 511 infants were included in the meta-analysis. Iron interventions had no significant effect on iron deficiency or iron deficiency anemia, serum ferritin level, or hemoglobin level. Iron interventions did result in a significant increase in Bayley psychomotor developmental indices in later life (mean difference [MD] = 7.00, confidence interval [95% CI] 0.99-13.01) and mean corpuscular volume (MD = 2.17 fL; 95% CI 0.99-3.35 fL). Iron supplementation was associated with slower growth during the exclusive breastfeeding period, but the long-term effect is unclear. CONCLUSIONS: Limited available evidence suggests that daily iron supplementation has beneficial effects on hematologic parameters and cognitive development, but may delay physical growth in healthy exclusively breastfed infants. There was no evidence to suggest that iron supplementation could cause other adverse effects.

Transcriptome analysis of the Brassica napus-Leptosphaeria maculans pathosystem identifies receptor, signaling and structural genes underlying plant resistance.

The hemibiotrophic fungal pathogen Leptosphaeria maculans is the causal agent of blackleg disease in Brassica napus (canola, oilseed rape) and causes significant loss of yield worldwide. While genetic resistance has been used to mitigate the disease by means of traditional breeding strategies, there is little knowledge about the genes that contribute to blackleg resistance. RNA sequencing and a streamlined bioinformatics pipeline identified unique genes and plant defense pathways specific to plant resistance in the B. napus-L. maculans LepR1-AvrLepR1 interaction over time. We complemented our temporal analyses by monitoring gene activity directly at the infection site using laser microdissection coupled to quantitative PCR. Finally, we characterized genes involved in plant resistance to blackleg in the Arabidopsis-L. maculans model pathosystem. Data reveal an accelerated activation of the plant transcriptome in resistant host cotyledons associated with transcripts coding for extracellular receptors and phytohormone signaling molecules. Functional characterization provides direct support for transcriptome data and positively identifies resistance regulators in the Brassicaceae. Spatial gradients of gene activity were identified in response to L. maculans proximal to the site of infection. This dataset provides unprecedented spatial and temporal resolution of the genes required for blackleg resistance and serves as a valuable resource for those interested in host-pathogen interactions.

A TgCRND8 Mouse Model of Alzheimer's Disease Exhibits Sexual Dimorphisms in Behavioral Indices of Cognitive Reserve.

Cognitive decline is sexually dimorphic in Alzheimer's disease (AD). Men show higher incidences of amnestic mild cognitive impairment yet women disproportionally phenoconvert to AD. It is hypothesized that men maintain greater cognitive reserve than women under comparable amyloid-ß (Aß) challenge. One behavioral aspect of cognitive reserve in mice is the capacity to cope with Aß-associated stereotypies by switching to increasingly effective navigational search strategies in the Morris water maze. To explore inherent sex differences in this paradigm, however, we require an AßPP mouse model wherein behavioral flexibility is impaired earlier in females than males despite equivalent Aß load. Here, we show that when F1 C57Bl/6×C3H/HeJ TgCRND8 mice are placed on C57Bl/6 background, N5 Tg males and females exhibit equivalent Aß pathologies at 2, 4, 6, and 8 months of age yet females display learning and memory deficits earlier than males. We further show that this N5 line does not carry the autosomal recessive pde6brd1 mutation that impairs visual acuity and that the estrous cycle is not disrupted on this genetic background. At 5.5 months of age, Tg males, but not females, compensate for Aß-associated stereotypic behaviors (i.e., hyperactive tight circling) by alternating navigational search strategies and adopting increasingly productive spatial search strategies. Females fail to overcome Aß-associated stereotypies and do not efficiently switch from systematic to spatial learning strategies. Together, these data identify a novel AßPP mouse model that can be used for preclinical testing of interventions targeting sexual dimorphisms in behavioral indices of cognitive reserve.

Phosphoproteome analysis of an early onset mouse model (TgCRND8) of Alzheimer's disease reveals temporal changes in neuronal and glia signaling pathways.

Sustained exposure to soluble amyloid ß (Aß42 ) oligomers is predicted to impair synaptic function in the hippocampal-entorhinal circuit, signaling synaptic loss and precipitating cognitive impairment in Alzheimer's disease. Regional changes in overall patterns of protein phosphorylation are likely crucial to promote transition from a presymptomatic to a symptomatic state in response to accumulating Aß42. Here, we used unbiased proteomic approaches to compare the phosphoproteome of presymptomatic and symptomatic TgCRND8 mice and identify network disruptions in signaling pathways implicated in the manifestation of behavioral indices of learning and memory impairment. Phosphopeptide enrichment with triple isotopic dimethylation labeling combined with online multidimensional separation and MS was used to profile phosphoproteome changes in 2- and 6-month-old TgCRND8 mice and congenic littermate controls. We identified 1026 phosphopeptides representing 1168 phosphorylation sites from 476 unique proteins. Of these, 595 phosphopeptides from 293 unique proteins were reliably quantified and 139 phosphopeptides were found to change significantly in the hippocampus of TgCRND8 mice following conversion from a presymptomatic to a symptomatic state.

Frontal and motor cortex oxygenation during maximal exercise in normoxia and hypoxia.

Reductions in prefrontal oxygenation near maximal exertion may limit exercise performance by impairing executive functions that influence the decision to stop exercising; however, whether deoxygenation also occurs in motor regions that more directly affect central motor drive is unknown. Multichannel near-infrared spectroscopy was used to compare changes in prefrontal, premotor, and motor cortices during exhaustive exercise. Twenty-three subjects performed two sequential, incremental cycle tests (25 W/min ramp) during acute hypoxia [79 Torr inspired Po(2) (Pi(O(2)))] and normoxia (117 Torr Pi(O(2))) in an environmental chamber. Test order was balanced, and subjects were blinded to chamber pressure. In normoxia, bilateral prefrontal oxygenation was maintained during low- and moderate-intensity exercise but dropped 9.0 +/- 10.7% (mean +/- SD, P < 0.05) before exhaustion (maximal power = 305 +/- 52 W). The pattern and magnitude of deoxygenation were similar in prefrontal, premotor, and motor regions (R(2) > 0.94). In hypoxia, prefrontal oxygenation was reduced 11.1 +/- 14.3% at rest (P < 0.01) and fell another 26.5 +/- 19.5% (P < 0.01) at exhaustion (maximal power = 256 +/- 38 W, P < 0.01). Correlations between regions were high (R(2) > 0.61), but deoxygenation was greater in prefrontal than premotor and motor regions (P < 0.05). Prefrontal, premotor, and motor cortex deoxygenation during high-intensity exercise may contribute to an integrative decision to stop exercise. The accelerated rate of cortical deoxygenation in hypoxia may hasten this effect.